BACKGROUND: The majority of two-stage prepectoral breast reconstruction has been described utilizing acellular dermal matrix (ADM). Although reports of prepectoral breast reconstruction without ADM exist, there is a paucity of comparative studies. METHODS: A single-institution retrospective review was performed of consecutive patients undergoing immediate prepectoral two-stage breast reconstruction with tissue expanders from 2017 to 2019. Short-term reconstructive and aesthetic complications were compared between cases that utilized ADM for support and those that did not. RESULTS: In total, 76 cases (51 patients) were identified, of which 35 cases utilized ADM and 41 did not. Risk factors and demographics were similar between the two cohorts with the exception of body mass index, which was higher in the ADM cohort (29.3 versus 25.4, = 0.011). Average follow-up length was also longer in patients who received ADM (20.3 versus 12.3 months, < 0.001). Intraoperative expander fill was higher in patients who did not receive ADM (296.8 cm versus 151.4 cm, < 0.001) though final implant size was comparable in both cohorts ( = 0.584). There was no significant difference in the rate of any complication between the ADM and no ADM cohorts (25.7% versus 17.1%, respectively = 0.357), including major mastectomy flap necrosis ( 0.245), major infection ( 1.000), seroma ( 0.620), expander explantation ( 1.000), capsular contracture ( 1.000), implant dystopia ( 1.000), and rippling ( 0.362). CONCLUSIONS: Immediate two-stage prepectoral breast reconstruction with tissue expanders has comparable rates of short-term complications with or without ADM support. Safety of prepectoral expander placement without ADM may warrant more selective ADM use in these cases.